The present invention relates to a bundle of hollow fibres for a device for treating blood or plasma by extracorporeal circulation, and to a process for producing a bundle of hollow fibres constituting the semi-permeable membrane of the device.
Membrane devices for treating blood or plasma by extracorporeal circulation are used in many different medical or paramedical applications, such as treating renal insufficiency by dialysis or haemofiltration, plasmapheresis and apheresis for therapeutic and non-therapeutic purposes, oxygenating blood, immunopurification, etc.
In general, semi-permeable membranes can be classified by their hydraulic permeability into low flux membranes, medium flux membranes and high flux membranes.
Hydraulic permeability describes the quantity of water that can be ultrafiltered through a semi-permeable membrane with a given active surface area, at a given transmembrane pressure over a given time period. Simultaneously with the water ultrafiltration, salts and toxins traverse the semi-permeable membrane. Eliminating the different solutes depends on a property of the membrane known as the rejection rate or transmittance (transmittance=1 or rejection rate=0 for solutes traversing the membrane with no change in concentration, rejection rate=100% and transmittance=0 for completely cleared solutes). The transmittance of a particular molecule is defined as the ratio of the concentration of the molecule in ultrafiltered water (ultrafiltrate) to its mean concentration in the unfiltered fraction of the blood.
With high flux semi-permeable membranes, i.e., with a hydraulic permeability of at least 31xc3x9710xe2x88x9212 m3/s.Pa.m2 (15 ml/h.mmHg.m2), the quantity of water extracted from the blood must be regulated using a water extraction controller. Devices provided with a high flux membrane run the risk of reverse filtration or back filtration, which consists of migration of a portion of the dialysis solution into the blood.
The dialysis solution, which has an electrolytic composition that is close to that of a normal extracellular liquid, is usually a non-sterile aqueous solution. Before use, the dialysis solution is normally free of solutes to be eliminated from the blood, but can contain foreign substances or pyrogenic substances, for example as a result of microbial contamination. Dialysis solution is not intended for injection into the blood and thus does not have the quality of an injectable liquid. With back filtration, then, there is then a risk of causing foreign or pyrogenic substances to enter the blood with the dialysis solution.
As is known, back filtration can be minimised by using semi-permeable low flux membranes with a hydraulic permeability of less than 12.5xc3x9710xe2x88x9212 m3/s.Pa.m2 (6 ml/h.mmHg.m2), or medium flux semi-permeable membranes with a permeability of between about 12.5 and about 31xc3x9710xe2x88x9212 m3/s.Pa.m2 (between about 6 and about 15 ml/h.mmHg.m2). However, the reduction in hydraulic permeability is generally accompanied by a reduction in transmittance, i.e., a reduction in the fraction of certain molecules that pass by convection through the pores of the membrane and which are intended to be eliminated from the blood.
Thus, one aim of the invention is to provide a device for treating blood or plasma by extracorporeal circulation, comprising a semi-permeable membrane with a reduced overall hydraulic permeability to limit the risks of reverse filtration, while retaining satisfactory transmittances, in particular those for toxins and proteins.
A further aim of the invention is to provide a device for treating blood or plasma by extracorporeal circulation comprising a semi-permeable membrane, the characteristics (hydraulic permeability, transmittances) of which can be adjusted independently of each other to a certain extent such that the hydraulic permeability of the membrane is low flux, medium flux or high flux, while the transmittances, in particular as regards toxins and proteins, are maintained at satisfactory values.
In a first aspect of the invention, these aims are achieved by a bundle of hollow fibres intended to constitute the semi-permeable membrane of a device for treating blood or plasma by extracorporeal circulation, in which:
the distribution of the hollow fibres in the bundle is heterogeneous; and
the internal diameter and wall thickness of the hollow fibres located in the zones most dense in hollow fibres are respectively greater than the internal diameter and wall thickness of the hollow fibres located in the least dense zones.
Preferably, the internal diameter and wall thickness of the hollow fibres located in the zones least dense in hollow fibres are respectively a minimum of 180 microns and 40 microns.
In a variation of the invention:
the heterogeneity of the distribution of the hollow fibres in the bundle corresponds to a higher density of hollow fibres around at least a portion of the periphery of the bundle compared with a density of hollow fibres at the centre of the bundle; and
the internal diameter and wall thickness of the hollow fibres located at the periphery of the bundle are respectively greater than the internal diameter and wall thickness of the hollow fibres located at the centre of the bundle.
In a second aspect of the present invention, the above aims are achieved by a bundle of hollow fibres intended to constitute the semi-permeable membrane of a device for treating blood or plasma by extracorporeal circulation, in which:
the hydraulic permeability of the hollow fibres in the bundle is heterogeneous; and
the ratio of the highest hydraulic permeability measured on some hollow fibres of the bundle to the lowest hydraulic permeability measured on other hollow fibres of the same bundle is at least about 5.
In a variation of the invention, the heterogeneity of the hydraulic permeability in the bundle corresponds to a higher hydraulic permeability around at least a portion of the periphery of the bundle compared with a hydraulic permeability of the bundle fibres, such that the ratio of the highest hydraulic permeability measured at the periphery of the bundle to the lowest hydraulic permeability measured at the centre of the bundle is at least about 5.
In a further variation of the invention, the heterogeneity of the hydraulic permeability is associated with a heterogeneity of the distribution of the hollow fibres in the bundle, the hydraulic permeability being higher in the zones most dense in hollow fibres and lower in the zones least dense in hollow fibres.
Advantageously, the internal diameter and wall thickness of the hollow fibres located in the zones most dense in hollow fibres are respectively greater than the internal diameter and wall thickness of the hollow fibres located in the zones least dense in hollow fibres. Advantageously again, the internal diameter and wall thickness of the hollow fibres located in the zones least dense in hollow fibres are respectively a minimum of 180 microns and 40 microns.
In one embodiment of the invention, the overall hydraulic permeability of the bundle of hollow fibres is in the range 10xc3x9710xe2x88x9212 to 312xc3x9710xe2x88x9212 m3/s.Pa.m2 (5 to 150 ml/h.mmHg.m2), the lowest hydraulic permeability measured at the centre of the bundle is less than 17xc3x9710xe2x88x9212 m3/s.Pa.m2 (8 ml/h.mmHg.m2) and the highest hydraulic permeability measured at the periphery of the bundle is more than 42xc3x9710xe2x88x9212 m3/s.Pa.m2 (20 ml/h.mmHg.m2).
In a further embodiment, the overall hydraulic permeability of the bundle of hollow fibres is in the range 42xc3x9710xe2x88x9212 to 146xc3x9710xe2x88x9212 m3/s.Pa.m2 (20 to 70 ml/h.mmHg.m2), the lowest hydraulic permeability measured at the centre of the bundle is less than 17xc3x9710xe2x88x9212 m3/s.Pa.m2 (8 ml/h.mmHg.m2), the highest hydraulic permeability measured at the periphery of the bundle is more than 83xc3x9710xe2x88x9212 m3/s.Pa.m2 (40 ml/h.mmHg.m2) and the ratio of the highest hydraulic permeability measured at the periphery of the bundle to the lowest hydraulic permeability measured at the centre of the bundle is at least 10.
Within the context of the present invention, the overall hydraulic permeability Lp of the bundle is conventionally obtained by measuring the filtration time t of a volume V of water at a mean transmembrane pressure P of the order of 50 to 500 mmHg through a surface area S of membrane at a given temperature (see European standard EN 12.83). The hydraulic permeability Lp is expressed in m3/s.Pa.m2 or ml/h.mmHg.m2 and corresponds to formula (I):
Lp=V/(tPS)xe2x80x83xe2x80x83(I)
To evaluate the heterogeneity of the hydraulic permeability of hollow fibres inside a bundle, within the context of the present invention a method has been developed for measuring the hydraulic permeability of a sub-group of hollow fibres of the bundle, the number of hollow fibres in the evaluated sub-group being substantially the same for each measurement. The hydraulic permeability of a sub-group of hollow fibres will be termed the xe2x80x9clocal hydraulic permeability Lpixe2x80x9d in the description. In general, the method for measuring the local hydraulic permeability Lpi of a sub-group of hollow fibres of a bundle of hollow fibres mounted in a tubular casing comprising a lateral opening at one of its ends, the bundle of hollow fibres being fixed in the casing by an adhesive seal at each of its ends, and the adhesive seals having been cut perpendicular to a longitudinal axis of the bundle to open the fibres, comprises the principal steps defined in claim 26 below. The conditions for this measurement are diagrammatically shown in the accompanying FIG. 1 and are described in detail below. The local hydraulic permeability Lpi measurements are preferably carried out on a ready-to-use hollow fibre device for the treatment of blood or plasma by extracorporeal circulation, i.e. after assembling the various components of the hollow fibre device, in particular by mounting bundle 1 of hollow fibres in a tubular casing 2 comprising, at each of its ends, a lateral opening 5 and 6 (inlet/outlet channel) and by setting seals 3 and 4, after having separated the hollow fibres from each other at their ends, for example by riffling or brushing their ends, manually or with a stream of air. This allows the ends of hollow fibres that have stuck together to be separated and eliminates the risk of leakage into the seal. As is well known, the sealing operation consists of securing the two ends of the bundle of hollow fibres by adhesive bonding using a seal in which a portion of the length of the fibres is embedded, the ends of the fibres being left open. Then the adhesive seals, in which the open ends of the hollow fibres are secured by adhesive and substantially uniformly distributed, are cut. To measure the local hydraulic permeability, casing 2 containing the bundle of hollow fibres is placed in a vertical position, and a seal is produced at the lower end of the casing (and as a result the lower cut surface of the bundle) by pressing it on a plate 11 to ensure a seal, for example a plate of a flexible plastics material such as a silicone. A liquid, for example water or a dialysis liquid, is then passed at a flow rate of 80 ml/min, for example, through the lower lateral opening 6 while the upper lateral opening 5 is closed. A calibrated tube 12, in the vertical position, is applied to a portion of the upper cut surface of the bundle to measure the local flow rate at the upper end of the casing. To carry out the measurement, calibrated tube 12 is firmly applied against the portion of the upper cut surface to be evaluated (in the figure, against the centre of the bundle of hollow fibres), to form an intimate connection between the upper cut surface and the calibrated tube 12. A flow of liquid is applied via lower lateral opening 6 of casing 2 and the time t that the liquid takes to pass from a given first graduation 13 to a second given graduation 14 provided on calibrated tube 12 is measured. From the local measured flow rate (corresponding to the defined volume V of tube 12 between the two graduations 13, 14 related to the time t for the liquid to pass from graduation 13 to graduation 14) and the known values of the transmembrane pressure P and the surface area Si of the hollow fibres in the sub-group on which the local flow rate is being measured, the local hydraulic permeability Lpi is measured using the following formula (II):
Lpi=V/(tPSi)xe2x80x83xe2x80x83(II).
The dimensions of the calibrated tube 12 are not critical. They are suitable to allow local measurement of the flow rate. Thus the diameter of calibrated tube 12 can be 3.2 cm and its height can be of the order of 50 cm.
It should be noted that the local hydraulic permeability measured with the above method corresponds in fact to back filtration (passage of liquid from the dialysate compartment to the blood compartment, as conventionally defined, in particular via the insides of the hollow fibres), but other tests carried out by the Applicant have shown that the value of the hydraulic permeability of the hollow fibres does not depend on the direction of passage of the liquid.
By carrying out local hydraulic permeability measurements over the whole of the upper cut surface of the bundle of hollow fibres, the local hydraulic permeability can be mapped to show the variation with measurement zone. In this respect, it should be noted that the number of hollow fibres evaluated during each local hydraulic permeability measurement is substantially constant. The operation of separating the hollow fibres from each other at their ends prior to sealing homogenises the hollow fibre density at the ends of the bundle.
In accordance with the present invention, the devices for treating blood or plasma by extracorporeal circulation contain a bundle composed of an assembly of hollow fibres that differ from each other by their hydraulic permeability, certain hollow fibres being low flux while other hollow fibres are high flux. Overall, devices according to the present invention have the advantage of being capable of being high flux, medium flux or low flux depending on the local hydraulic permeabilities of the hollow fibres in the bundle.
The devices of the invention have the further advantage of having higher transmittance values than those obtained with conventional devices with an equivalent hydraulic permeability.
Thus, in the present invention, the devices can have a transmittance for cytochrome C of about 0.1 to about 0.6 (measured under the conditions specified in standard EN 12.83) with overall hydraulic permeability values of 20xc3x9710xe2x88x9212 to 312xc3x9710xe2x88x9212 m3/s.Pa.m2 (10 to 150 ml/h.mmHg.m2).
In a variation of the invention, to produce the hollow fibre devices of the invention, hollow fibres consisting mainly of polyarylsulphone are selected. Preferably, they contain repeating units with formula (I) or (II) below: 
The polyarylsulphone with formula (I), the chain of which contains alkyl radicals, in particular methyl radicals, is termed a polysulphone. The polyarylsulphone with formula (II), which simply contains aryl radicals connected together by an ether or a sulphone group, is termed polyethersulphone.
The invention also pertains to a process for producing a bundle of hollow fibres consisting mainly of polarylsulphone, useful as a semi-permeable membrane in a device for treating blood or plasma by extracorporeal circulation, the process comprising the following steps:
(a) preparing a bundle of hollow fibres with a heterogeneous distribution of fibres within the bundle insofar as the density of the hollow fibres is higher in certain zones of the bundle than in other zones;
(b) mounting the bundle of hollow fibres in a tubular casing comprising two axial openings;
(c) causing a hot, dry gas that is chemically inert towards the hollow fibres, preferably hot, dry air, to circulate through the bundle of hollow fibres, not held at its ends, at a temperature and flow rate that are suitable to cause geometrical heterogeneity of the hollow fibres in the bundle as regards the internal diameter and wall thickness of the hollow fibres;
(d) stopping the hot, dry gas from circulating when the geometrical heterogeneity of the hollow fibres has been obtained.
Adjusting the operating conditions of steps a) and c) affects the characteristics of devices for extracorporeal treatment of blood, in particular the hydraulic permeabilities.
The term xe2x80x9chot, dry gasxe2x80x9d as used in the context of the present invention means a hot gas with a relative humidity that does not exceed 10% at the temperature at which the gas is used. Preferably, the temperature of the hot, dry gas at the inlet to the bundle of hollow fibres is 75xc2x0 C. to 130xc2x0 C., more preferably 90xc2x0 C. to 120xc2x0 C.
Preferably, the flow rate of the hot, dry gas at the inlet to the bundle of hollow fibres is 2 to 5 m3 per hour.
Preferably, the duration of step (c), consisting of circulating a hot, dry gas through the bundle of hollow fibres, is of the order of 1 to 4 hours.
Preferably, circulation of the hot, dry gas is stopped when the temperature of the gas at the outlet from the tubular casing is substantially equal to the temperature of the gas at the inlet to the tubular casing.
The invention also concerns a bundle of hollow fibres resulting from carrying out the production process described above.
Further characteristics and advantages of the invention will become apparent from the detailed description below, concerning variations and embodiments of the present invention.